Pathogenesis of Hirschsprung’s disease and its variants: recent progress

https://doi.org/10.1053/j.sempedsurg.2003.09.004Get rights and content

Abstract

The enteric nervous system (ENS) is a complex network of interconnected neurons within the wall of the intestine that controls intestinal motility, regulates mucosal secretion and blood flow, and also modulates sensation from the gut. The cells that form the ENS in mammals are derived primarily from vagal neural crest cells. During the past decade there has been an explosion of information about genes that control the development of neural crest. Molecular-genetic analysis has identified several genes that have a role in the development of Hirschsprung’s disease. The major susceptibility gene is RET, which is also involved in multiple endocrine neoplasia type 2. Recently, genetic studies have provided strong evidence in animal models that intestinal neuronal dysplasia (IND) is a real entity. HOX11L1 knockout mice and endothelin B receptor-deficient rats demonstrated abnormalities of the ENS resembling IND type B in humans. These findings support the concept that IND may be linked to a genetic defect.

Section snippets

Development of the enteric nervous system

The enteric nervous system (ENS) is the largest and the most complex division of the peripheral nervous system.34, 35 The ENS contains more neurons than the spinal cord and is responsible for the coordination of normal bowel motility and secretory activities.36 As our understanding of the ENS improves, it becomes clear that it is no longer sufficient to simply determine whether enteric ganglion cells are present. We are learning the importance of determining whether the correct number and types

Genes involved in ENS development and HSCR

Genetic factors have been implicated in the aetiology of HSCR. HSCR is known to occur in families. The reported incidence of familial cases in rectosigmoid HSCR varied from 3.6% to 7.8% in different series.1 A familial incidence of 15% to 21% has been reported in total colonic aganglionosis and 50% in the rare total intestinal aganglionosis.4, 46 Schiller et al47 reported 22 infants belonging to four families from Gaza, who had either documented or clinically suspected HSCR. Of these infants,

RET/GDNF/GFRα1 signaling system

This signaling pathway is of importance for subpopulations of both peripheral and central neurons, having been shown by in vitro and in vivo assays to promote survival of neurons, mitosis of neuronal progenitor cells, differentiation of neurons and neurite extension.34, 51, 52 The RET receptor is the signaling component of receptor complexes with four ligands, glial-derived neurotropic factor (GDNF), neurturin (NTN), artemin (ATM), and persephin (PSP)34, 36 (Fig 1). The complete receptor

Endothelin signaling pathway

The endothelins (EDN1, EDN2, and EDN3) are intercellular local messengers that act via cell surface receptors, EDNRA and EDNRB.34 EDNRA shows high affinity binding for EDN1 and does not bind EDN3 at physiologic concentrations, whereas EDNRB accepts all these ligands with high affinity.36 EDN is initially produced as an inactive preproendothelin that undergoes two proteolytic steps to produce an active peptide. The first cleavage produces inactive big endothelins, and these are finally cleaved

SOX10

A comparative study of human/mouse sequences led to the identification of a new member of the SRY/Sry-like, high mobility group box gene family, SOX10. It is expressed by ENS precursors before and throughout colonization of the gut mesenchyme.36 The involvement of SOX10 in the development of enteric neurons was demonstrated in the Dom (Dominant megacolon) mouse model of HSCR.89, 90 SOX10, Dom/+ mice exhibit distal intestinal aganglionosis, they die shortly after birth and they are a naturally

PHOX2B

Phox2B gene is a homeodomain-containing transcription factor that is involved in neurogenesis and regulates RET expression in mice,92 in which disruption of the Phox2B gene results in a HSCR-like phenotype.93 Enteric Phox 2B expression begins in vagal and truncal NC-derived cells as they invade the foregut mesenchyme and is contained in the adult submucosal and myenteric plexus.36, 93 Recently, Garcia-Bercelo et al reported that Phox2B A-G1364 polymorphism may predispose to HSCR.94

Genes associated with intestinal neuronal dysplasia

IND type B (INDB) is often encountered in children presenting with intractable constipation and grossly abnormal intestinal transit time and ENS abnormalities.11, 12, 13, 14, 15 Many investigators have raised doubts about the existence of IND as a distinct histopathologic entity.27, 28, 29 It has been suggested that the pathologic changes seen in IND may be part of normal development or may be secondary phenomenon induced by congenital obstruction and inflammatory disease.28, 30 Recently,

HOX11L1

Hox11L1 is a homebox gene involved in peripheral nervous system development and is reported to play a role in the proliferation or differentiation of NC cell lines. Two different Hox11L1 knockout mouse models have been generated.31, 32 In both cases, homozygous mutant mice were viable but developed megacolon at the age of 3 to 5 weeks. Histological and immunohistochemical analysis showed hyperplasia of myenteric ganglia, a phenotype similar to that observed in human INDB. However, the mutation

EDNRB gene

Ontogenetic studies revealed that mutations in the EDNRB gene or its specific ligand endothelin-3 (EDN3) lead to defects in the development of NC cells.76, 77 When colonization of the gut by NC cells is incomplete, the distal part of the bowel is left aganglionic. Recently Von Boyen et al33 reported abnormalities of the ENS in heterozygous EDNRB-deficient rats resembling IND in humans. They showed that a heterozygous 301 bp deletion of the EDNRB gene led to abnormalities of the ENS.

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